Mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd)

ABSTRACT

The present invention relates to a modified-release composition of mazindol and its use in the treatment of attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alertness (i.e., incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (e.g., narcolepsy, idiopathic hypersomnia) in particular in children, adolescents and adults.

Priority benefit is claimed under 35 U.S.C. § 119 to PCT Application No.PCT/EP2016/055048, filed on Mar. 9, 2016, at the European Patent Office,The Hague, which PCT Application is hereby incorporated by reference inits entirety. Priority benefit is also claimed under 35 U.S.C. § 119(e)to U.S. Provisional Application No. 62/305,600, filed on Mar. 9, 2016,and is incorporated by reference in its entirety.

The present invention relates to a modified-release composition ofmazindol and its use in the treatment of attention deficit disorders(ADD) or attention deficit/hyperactivity disorder (ADHD) or relateddeficit of alertness (i.e., incoercible sleepiness) or decline ofvigilance (i.e., daytime somnolence) or excessive daytime sleepiness(e.g., narcolepsy, idiopathic hypersomnia) in particular in children,adolescents and adults.

ADHD is a behavioural disorder that constitutes one of the mostfrequently encountered patterns in child and adolescent psychopathology.It is also present in adults. Although a recent longitudinal studyraises possibility that adults presenting with the ADHD symptom picturemay not have a childhood-onset neurodevelopmental disorder (Moffitt2015), the majority of available data and scientific consensus suggestthat ADHD is the same disease in both adults and pediatrics (Kooji 2010)In fact, the criteria for ADHD was changed in DSM-V (AmericanPsychiatric Association, 2013) to more accurately characterize ADHD as aneurodevelopmental disorder, which begins in childhood but continuesthrough adulthood for some people. In recent studies the prevalence ofADHD is estimated to be 7 to 8% of school-age children (Barbaresi 2002)and 4 to 5% of adults (Kessler 2006). Clinically, this disorder combinesinattention, impulsivity and motor hyperactivity leading to impairmentin academic/work, social and interpersonal functioning. Withouttreatment, children and adults are unable to stay on task leading todecreased academic or work performance. In addition, impulsivity maylead to decreased quality of work and dysfunctional social functioning.

The stimulants used, and commonly accepted in the pharmacologicaltreatment of ADHD, belong to several pharmacological classes:psychostimulants (amphetamine, methylphenidate), eugregorics(armodafinil, modafinil, adrafinil), nonstimulatnts (atomoxetine,clonidine and guanfacine), and inhibitors of mono-amine oxydase B(selegiline). The improvement of inattention, impulsivity, andhyperactivity by such dopaminergic psychostimulants is often verysignificant, but nevertheless insufficient in many subjects.

Stimulants (e.g., methylphenidate or amphetamines salts) have shorthalf-lives and require controlled release delivery in the majority ofpatients. Even with controlled delivery, it is difficult to maintainadequate efficacy during school (and/or work) hours and yet achieveconcentrations that will allow the patient to fall asleep and remainasleep at night. Stimulants are associated with the appearance of“on-off” effects, where the coming-off effect is accompanied by a“symptom rebound” effect with a worsening of the symptoms in the earlyevening (e.g., a time when homework needs to be completed).

While stimulant medication is an effective treatment for many of thesymptoms associated with ADHD, there are concerns about diversion ofthese medications for misuse and abuse, and some rare but seriouscardiovascular side-effects can occur with the use of stimulantmedication. Non-stimulants such as atomoxetine, clonidine and guanfacinehave also been found to be efficacious in treating ADHD but the efficacyof these agents may not be comparable to that seen with stimulants(Faraone 2009). Even with stimulant treatment, optimal functioningoccurs in only roughly one in four children with ADHD (Greenhill 1996).Despite considerable advances in our understanding and treatment ofADHD, the disorder remains difficult to manage and further treatmentoptions need to be developed (Antshel 2011). In addition, some of themedications administered in the treatment of ADHD are not suited foradministration to children, especially because of excessive size of thetablets or the administration of the medications several times a day.

Use of mazindol in treatment of attention deficit/hyperactivity disorder(ADHD), according to DSM-IV (or DSM-V) criteria, comprisingadministering an effective amount of mazindol to a patient in need ofsuch treatment has been described in U.S. Pat. No. 8,293,779. Mazindolhas the following chemical formula:5-(4-chlorophenyl)-2,5-dihydro-3H-imadazo[2,1-a]isoindol-5-ol

Mazindol is considered, in current medication classifications, as apsychoanaleptic and anorexigenic medication. It is currently authorizedin Argentina, Mexico/Central America, and Japan for use in the treatmentof obesity.

The essential pharmacological action of mazindol, in all speciesstudied, in healthy animals and in humans, is hypothalamic, on theappetite-regulating dopaminergic centres (Hadler, 1972). It ismetabolized extensively and the metabolites are then mostly excreted inthe urine. Mazindol is a non-amphetamine compound because of itstricyclic chemical structure. It offers a pharmacological profile veryclose to that of amphetamines with less abuse liability. Indeed,mazindol is not metabolised to an amphetamine-like compound, but it actsby blocking the dopamine and norepinephrine reuptake similarly toamphetamine.

In addition, in animal toxicology studies, the toxic potential ofmazindol has proved to be very low In particular, no carcinogeniceffect, no mutagenic effect, and no toxicology effect in reproductionwas observed.

In U.S. Pat. No. 8,293,779, it is disclosed that, after single orrepeated oral administration, mazindol is absorbed with a time tomaximum concentrations (Tmax) of 2-4 hours. The half-life of mazindolafter an immediate release formulation is 9.1±1.7 h in healthyvolunteers (Kim 2009); therefore, steady-state concentrations arereached after approximately 30-55 hours. The pharmacokinetics is linear(independent of the dose) for doses of between 1 mg/day and 4 mg/day.This result however relates to current immediate-release formulations ofmazindol.

Immediate-release pharmaceutical compositions of mazindol, such asDiminex®, Sanorex® and Teronac®, ensure the release of the activeingredient over a period of <1 h in vitro. Indeed, immediate-releasepharmaceutical compositions of mazindol have been reported to undergohydrolysis at moderate temperatures in neutral and alkaline aqueoussolutions, including in human plasma. Due to the mild alkaline nature ofplasma, improved mazindol stability in human plasma is achieved byadding acidic buffer.

Such immediate release compositions thus require twice dailyadministration, which limits compliance in the special case of childrenof school age, as the second administration is often requested to bedone at midday, i.e. during school time. Even given the fact that theimmediate release tablet undergoes complete in vitro dissolution within1 hour, the time to maximum concentrations (Tmax) occurs at 3-4 hoursafter drug administration in healthy volunteers (Kim 2009). Rapidinitial absorption will allow the earlier achievement of adequatesystemic exposure to achieve desired efficacy (e.g., administer earlyand have onset of efficacy 1-2 hours later, when patient is at school orwork).

International Publication No. WO2001/123496 to Kidane et al. (2011)discloses formulations of mazindol with the objective of having mazindolbe absorbed in high pH environments, such as the colon. Theseformulations are primarily directed to encapsulated pellets that can beimmediate release, extended release, or delayed release. Theformulations disclosed in Kidane, being designed with enteric coatingsto release mazindol at higher pH, such as 6.8 (see, e.g., Examples 2, 3,9, and 12), will provide dissolution and release late in the smallintestine, which would likely result in a significant portion of thedrug not being released prior to reaching the colon. (Fallingborg J.).Since clinical pharmacokinetic studies have shown that mazindol is notlikely to be absorbed in the colon and mazindol's solubility decreaseswith increasing pH (i.e., most soluble at the pH of the stomach andleast soluble in the colon, particularly where water is less availabledue to reabsorption), these formulations likely result in a significantreduction of the availability of absorbable, dissolved mazindol.

To achieve once daily dosing regimen (a very desirable regimen), abetter controlled release portion would also be needed to assure thatadequate plasma concentrations are achieved throughout the day andevening, while allowing the subject to fall asleep and remain asleepduring the night. Thus, there is a need for a pharmaceutical compositioncomprising mazindol with an improved release profile of active substancecombining an immediate and a sustained release, an improved compliancefor patients, and reduced fluctuation in steady-state mazindol plasmaconcentrations during a dosing interval.

SUMMARY

According to a first aspect, the present invention thus relates to amazindol oral pharmaceutical unit dosage form in the form of amultilayer matrix-type tablet comprising:

-   -   at least one immediate-release (IR) layer comprising mazindol        and at least one diluent,    -   at least one sustained-release (SR) layer comprising mazindol        and at least one sustained-release, pH-independent and        water-insoluble polymer,        for a total amount of mazindol comprised between 1 and 6 mg and        a ratio in weight between the IR layers and the SR layers        comprised between 40:60 and 80:20 preferably between 50:50 and        70:30, more preferably of 50:50.

The oral pharmaceutical unit dosage form in the form of a multilayermatrix-type tablet of the invention provides a rapid release of drug toachieve a rapid therapeutic blood level and a sustained release portionto provide a continual release of mazindol available for absorption intothe patients' blood stream to achieve a prolonged therapeutic effect.This combination thus achieves a once daily regimen for the product.This oral pharmaceutical unit dosage form has the following advantages:

Ease of swallowing;

Ease of manufacture;

The ability to control the release rate of the drug by modifying thecomponents of each separate layer;

Superior stability compared to other dose forms, such as capsules,liquids;

Prevents patient tampering with the dose form;

Reduced fluctuation in steady-state mazindol plasma concentrationsduring a dosing interval;

Enhanced stability;

Onset within 1-2 hours, while not unnecessarily delaying consumption offood; and

Muted increase in heart rate.

According to another aspect, the invention relates to a process forpreparing the unit dosage form according to the invention, comprisingthe following steps:

-   -   (a) preparing the blend of the excipients of the IR layers,    -   (a′) preparing the blend of the excipients of the SR layers,    -   (b) adding the IR blend of step (a) and the SR blend of step        (a′) into a multilayer, preferably a bilayer, tablets' press.

According to a further aspect, the invention relates to the unit dosageform according to the invention, for its use as medicinal productadministered in repeat once-a-day form via oral route.

According to a further aspect, the invention relates to the unit dosageform according to the invention, for use for treating attention deficitdisorders (ADD) or attention deficit/hyperactivity disorder (ADHD) orrelated deficit of alertness (i.e., incoercible sleepiness) or declineof vigilance (i.e., daytime somnolence) or excessive daytime sleepiness(e.g., narcolepsy, idiopathic hypersomnia) in particular in children,adolescents and adults.

According to a further aspect, the invention relates to a method fortreating attention deficit disorders (ADD) or attentiondeficit/hyperactivity disorder (ADHD) or related deficit of alertness(i.e., incoercible sleepiness) or decline of vigilance (i.e., daytimesomnolence) or excessive daytime sleepiness (e.g., narcolepsy,idiopathic hypersomnia) comprising the administration, preferably inrepeat once-a-day via oral route, of the unit dosage form according tothe invention to a patient in need thereof, in particular in children,adolescents and adults.

According to a further aspect of the present invention, the inventionrelates to the unit dosage form according to the invention, used incombination with iron as a combination product for simultaneous,separate or sequential use, in particular for treating attention deficitdisorders (ADD) or attention deficit/hyperactivity disorder (ADHD) orrelated deficit of alertness (i.e., incoercible sleepiness) or declineof vigilance (i.e., daytime somnolence) or excessive daytime sleepiness(e.g., narcolepsy, idiopathic hypersomnia) in particular in children,adolescents and adults.

According to a further aspect, the invention relates to a method fortreating attention deficit disorders (ADD) or attentiondeficit/hyperactivity disorder (ADHD) or related deficit of alertness(i.e., incoercible sleepiness) or decline of vigilance (i.e., daytimesomnolence) or excessive daytime sleepiness (e.g., narcolepsy,idiopathic hypersomnia) comprising the administration, preferably inrepeat once-a-day via oral route, of the unit dosage form according tothe invention and the administration of iron to a patient in needthereof, in particular in children, adolescents and adults.

According to a further aspect of the present invention, the inventionrelates to the unit dosage form according to the invention, used incombination with a psychostimulant as a combination product forsimultaneous, separate or sequential use, in particular for treatingattention deficit disorders (ADD) or attention deficit/hyperactivitydisorder (ADHD) or related deficit of alertness (i.e., incoerciblesleepiness) or decline of vigilance (i.e., daytime somnolence) orexcessive daytime sleepiness (e.g., narcolepsy, idiopathic hypersomnia)in particular in children, adolescents and adults.

According to a further aspect, the invention relates to a method fortreating attention deficit disorders (ADD) or attentiondeficit/hyperactivity disorder (ADHD) or related deficit of alertness(i.e., incoercible sleepiness) or decline of vigilance (i.e., daytimesomnolence) or excessive daytime sleepiness (e.g., narcolepsy,idiopathic hypersomnia) comprising the administration, preferably inrepeat once-a-day, via oral route of the unit dosage form according tothe invention and the administration of a psychostimulant to a patientin need thereof, in particular in children, adolescents and adults.

Definitions

The term “matrix-type tablet” is used in the invention to designate atablet whose inner structure in each layer is homogeneous and identicalfrom the center towards the periphery of the layer. Therefore, thelayers of the tablets of the present invention consist of a homogeneousmixture of active ingredient in powder or granule form and of acompression matrix.

The term “compression matrix” in the present invention is used todesignate all the excipients which take part in the cohesion of thetablet. Said compression matrix is both water-insoluble and has acertain permeability (hydrophilic matrix) or porous network (inertmatrix) responsible for the sustained release of the active ingredient,which does not vary in relation to the pH conditions of the medium. Theterm “compression mixture” is used in the present application todesignate all the constituents of the tablets (the active ingredient(s),granulated or not, and the constituents of the compression matrix)before its compression in tablet form.

As used in the present invention, the term “Cmax” refers to the maximumconcentration in the plasma after a single dose and Cmax(ss) refers tothe Cmax at steady-state. The Cmax and Cmax(ss) are lower with thiscontrolled release formulation.

As used in the present invention, the term “steady-state” refers to theconcentrations in the body after 4 to 7 half-lives after repeat dosing.The concentrations at steady-state differ depending on the formulationused and the dosing frequency. At steady state, plasma concentrations ofmazindol will vary between Cmax(ss) and Cmin(ss) (the minimum observedconcentration at steady-state).

A study with repeat doses not only provides a measure of the usualpharmacokinetic parameters (area under the curve during a dosinginterval at steady-state, AUC(0−τ), Cmax(ss), the time to the Cmax orCmax(ss), Tmax), but also demonstrates the significance of thefluctuations between the steady-state peak (Cmax(ss)) and trough(Cmin(ss)) concentrations.

Tmax is the time to reach the peak concentration. This value isdependent on the absorption rate of a pharmaceutically active material.The pharmacokinetic parameters Cmax, Cmax(ss), and Tmax result directlyfrom experimental plots. Repeat dosing with a drug can involve a certainaccumulation of the drug, or its metabolites, the significance of whichdepends on the dosage schedule used.

Given a drug M, administered orally at a dose D at a dosing timeinterval T. As the drug is given before the previous dose is fullyeliminated, the amount administered adds to the non-eliminated amountfrom the previous doses (superimposition principle). After a period of4-7 half-lives, the amount of drug absorbed that enters the body isequivalent to the amount that is eliminated from the body and steadystate is achieved. Concentrations vary between a trough concentrationCmin(ss) and a peak concentration Cmax(ss). As used in the presentinvention, “repeat oral dosing” refers to administration of theformulation of the present invention at a dose D at a dosing timeinterval r of between 20 and 24 hours.

The “fluctuation” and “swing” parameters are expressed as a % and arecalculated according to the following equations:

Fluctuation: 100*(Cmax(ss)−Cmin(ss))/Cav

wherein Cav is the “average steady-state concentration”, representingthe AUC(0−τ) divided by the dosing interval: Cav=AUC(0−τ)/τ.

In the meaning of the present invention, the expression «reduction offluctuations» may designate the lowering of the difference between theCmax(ss) and Cmin(ss) or differences between the peaks and troughs, orpreferably a value for the «fluctuation» parameter of between 25% and75% in one embodiment, <60% in one embodiment, <50% in one embodiment,or more preferably less than 35%.

Swing: 100*(Cmax(ss)−Cmin(ss))/Cmin(ss)=Δ

The half-life (t½) is the time for a concentration C of a drug in a bodyfluid or a tissue to reach the concentration C/2.

The area under the curve during a dosing interval at stead-state,AUC(0−τ), corresponds to the integral of the plasma concentration over agiven dosing interval. The AUC(0−τ) is expressed in units of mass (mg,ng)×liter (or mL)⁻¹×hour, and is dependent on the bioavailability andclearance of a drug.

In the meaning of the present invention, by a profile having «reducedfluctuation» is meant a profile having a swing Δ of less than 50% in oneembodiment or <60% in one embodiment, or <35% in one embodiment.

In the meaning of the present invention, by a profile having «reducedfluctuation» is also meant a plasma profile maintained above 40% orpreferably above 50% of the Cmax(ss) value for at least 12 hours.

An “immediate-release (IR) layer” refers to a layer that releasesgreater than or equal to about 80% by weight of mazindol in less than orequal to about 1 hour.

A “sustained-release (SR) layer” means a layer in which mazindol isreleased at a rate slower than that of an IR layer.

FIGURES

FIGS. 1-6 depict dissolution profiles of the prototype tablets ofExample 3.

FIG. 1: Overlay of All Dissolution Profiles

FIG. 2: Overlay of Series 1 Formulations

FIG. 3: Overlay of Series 2 Formulations

FIG. 4: Overlay of Dissolution Profiles for 50/50 IR/SR Ratio TabletFormulations

FIG. 5: Overlay of Dissolution Profiles for 60/40 IR/SR Ratio TabletFormulations

FIG. 6: Overlay of Dissolution Profiles for 70/30 IR/SR Ratio TabletFormulations

FIG. 7: Overlay of Dissolution Profiles from Batch 100-15021 TabletsAnalyzed Using UV Probes (100-15021) and HPLC Analysis (15021LC)

FIG. 8: Overlay of Dissolution Profiles from Batch 100-15022 TabletsAnalyzed Using UV Probes (100-15022) and HPLC Analysis (15022LC)

DETAILED DESCRIPTION

The pharmaceutical composition according to the present invention is amazindol oral pharmaceutical unit dosage form in the form of amultilayer matrix-type tablet comprising:

-   -   at least one immediate-release (IR) layer comprising mazindol        and at least one diluent,    -   at least one sustained-release (SR) layer comprising mazindol        and at least one sustained-release, pH-independent and        water-insoluble polymer,        for a total amount of mazindol comprised between 1 and 5 mg and        a ratio in weight between the IR layers and the SR layers        comprised between 40:60 and 80:20 preferably between 50:50 and        70:30, more preferably of 50:50. Preferably, the unit dosage        form according to the invention is a bilayer tablet.

In an embodiment of formulation of the invention, the dissolution ofmazindol can be between 60% and 80% at 1 hour and between 70% and 90% at2 hours, as measured in accordance with the rotating blade method at 50rpm according to the US Pharmacopeia Method 2, in a dissolution medium0.01N HCl, 500 mL. In another embodiment, a unit dosage form accordingto the invention can have a dissolution of 50%-65% at 0.5 hours, 55%-85%at 1 hour, 65%-95% at 2 hours, not less than 75% at 4 hours, and notless than 85% at 8 hours.

Preferably, the unit dosage form according to the invention is ofbetween 50 and 200 mg, preferably of 100 mg. Preferably, the unit dosageform according to the invention comprises between 2 and 5 mg ofmazindol, preferably of between 1 and 3 mg, more preferably of 4 mg.

Preferably, the unit dosage form according to the invention maintainsthe steady-state mazindol plasma concentrations obtained in vivo with areduced fluctuation of above 40% of the Cmax(ss) value, preferably above50% of the Cmax(ss) value, and preferably above 60% of the Cmax(ss) forat least 12 h.

Examples of diluents include: lactose, monohydrate lactose, anhydrouslactose, spray-dried lactose, calcium carbonate, calcium sulfate,calcium sulfate dehydrate, calcium lactate trihydrate, monobasic calciumsulfate monohydrate, calcium carbonate, tribasic calcium phosphate,diabasic calcium phosphate, compressible sugars, dextrates, dextrin,dextrose, calcium phosphate, kaolin, magnesium carbonate, magnesiumoxide, maltodextrin, mannitol, powdered cellulose, starch, modifiedstarch, starch hydrolyzates, pregelatinized starch, microcrystallinecellulose, powdered cellulose, cellulose and cellulose derivatives,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose and sucrose,preferably lactose, anhydrous lactose, spray-dried lactose,microcrystalline cellulose, powdered cellulose, cellulose and cellulosederivatives.

Diluent concentration in the IR layers can be varied between 1 and 95%,preferably 30 and 60%, more preferably 45 to 55% by weight of the totalweight of the IR layers.

Preferably, a unit dosage form according to the invention comprises alubricant in each layer.

Lubricants and glidants can be employed in the present application toprevent, reduce or inhibit adhesion or friction of ingredients of thecomposition. They facilitate the compression and ejection of compressedcompositions from a desired die. They are compatible with theingredients of the pharmaceutical composition, and they do notsignificantly reduce the solubility, hardness, chemical stability,physical stability, or the biological activity of the pharmaceuticalcomposition. The pharmaceutically acceptable lubricants and glidants forthe present application are selected from the group including but notlimited to stearic acid, metallic stearates, zinc stearate, magnesiumstearate, magnesium trisilicate, calcium hydroxide, tribasic calciumphosphate, magnesium carbonate, magnesium oxide, calcium stearate,glyceryl monostearate, waxes, glycerides, glyceryl behenate, glycerylpalmitostearate, silicone oil, hydrogenated vegetable oil, hydrogenatedcastor oil, light mineral oil, mineral oil, polyethylene glycol,methoxypolyethylene glycol, sodium acetate, sodium oleate, sodiumchloride, leucine, sodium benzoate, alkyl sulfates, sodium laurylsulfate, sodium stearyl fumarate, talc, colloidal silica, corn starch,powdered cellulose, and/or boric acid. The preferred range oflubricants/glidants is from 0% to 1% w/w of the layer.

The sustained-release, pH-independent and water-insoluble polymer in SRlayers of the tablets according to the invention is selected in thegroup consisting of cellulose polymers, high-molecular-weight polymersof acrylic acid that are crosslinked with either allyl sucrose or allylethers of pentaerythritol (Carbopol, Carbomers), polymers from the classof methacrylic acids, polyvinylalcohol derivatives, polymers of lacticand glycolic acids (PLGA), starches, waxes, polyvinyl acetatederivatives, polyvinyl pyrrolidone derivatives and mixtures thereof,preferably is selected in the group consisting of cellulose polymers andhigh-molecular-weight polymers of acrylic acid that are crosslinked witheither allyl sucrose or allyl ethers of pentaerythritol (Carbopol,Carbomers).

Cellulose polymers include hydroxypropyl methylcellulose (HPMC),hydroxypropyl cellulose (HPC), sodium CMC, ethyl cellulose derivativessuch as cellulose acetate, cellulose acetate butyrate, cellulose acetatecellulose propionate, hydroxypropylmethylcellulose acetate succinate,microcrystalline cellulose (for example such as the one supplied underthe trade mark Avicel®, and ethylcellulose (for example the one suppliedunder the trade mark Aqualon® ethylcellulose).

Polymers from the class of methacrylic acids include the gradesEudragit®RL 12.5, RL PO and RL 100 and RS 12.5, RS PO and RS 100.Starches include natural starches e.g. corn starches and modifiedstarches such as pre-gelled starch. Waxes include white or yellowbeeswax, polyvinyl acetate derivatives.

Sustained-release, pH-independent and water-insoluble polymerconcentration in the SR layers can be varied between 80 and 99%,preferably 90 to 97% by weight of the total weight of the SR layers.

The unit dosage form according to the invention can includeanti-agglomerant agents. anti-agglomerant agents used in the presentinvention include talc, silicon dioxide and its derivatives, acrylicesters, castor oil derivative, cellulose compounds, iron oxides,magnesium stearate, stearic acid and or sodium stearate.

Layers of the tablet according to the present invention can comprise abinder. Binders according to the invention, includehydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),maltodextrin, polyvinylpyrrolidone (PVP) and or microcrystallinecellulose.

The compression matrix can advantageously include, additionally to theexcipients of the compression matrix, one or more excipients intendedeither to promote the proper conducting of the compression process.

A metabolite of mazindol, referred to as2-(2-aminoethyl)-3-(p-chlorophenyl)-3-hydroxyphthalimidine or2-(p-Chlorobenzoyl)-N-2-(aminoethyl)benzamide), has a Cmax that isapproximately ¼ that of mazindol and a half-life that is longer thanmazindol. It may accumulate and contribute to the efficacy of mazindol,particularly at steady-state. A dose of 0.25 mg to 12 mg of thismetabolite may be used in the treatment of narcolepsy or ADHD.

The invention also relates to a process for preparing the unit dosageform according to the invention, comprising the following steps:

-   -   (a) preparing the blend of the excipients of the IR layers,    -   (a′) preparing the blend of the excipients of the SR layers,    -   (b) adding the IR blend of step (a) and the SR blend of step        (a′) into a multilayer, preferably a bilayer, tablet press.

Mazindol undergoes hydrolysis at moderate temperatures with minimalamount of water. Elimination of water in a mazindol formulationtherefore provides better stability. In preparing a unit dosage of theinvention, preferably no water is added to the process. In one aspect ofthis invention, a mazindol formulation is provided that is substantiallyfree of water, such that the amount of water by weight is less than1.5%, 1%, or preferably less than 0.5%. Because the preferred processfor formulating the bilayer or multilayer tablets of the presentinvention does not use water, it effectively eliminates moisture andconsequently provides better stability to the bilayer or multilayertableted formulations of the present invention. Moreover, the bilayer ormultilayer design of the present invention provides better homogeneityand less variation in tablet uniformity to deliver consistency in theamount of the mazindol in the tablet and ultimately administered.

In the context of the present invention, the diagnosis ofattention-deficit/hyperactivity disorder (ADHD) is based on the clinicalcharacteristics defined by the international classification used byICD-10 (International Classification of Diseases (ICD). World HealthOrganization) and DSM-V (Diagnostic and Statistical Manual of MentalDisorders, 5^(th) edition).

The criteria of DSM-V includes three dimensions (inattention,impulsivity and hyperactivity), normal intellectual efficiency (IQ>80)and having isolated iron deficiency, but not anemic, that is to sayhaving a normal haemoglobin level. The expression “iron deficiency”means hypoferrinaemia without significant modification to the serumconcentration of soluble transferrin receptors.

“ADHD symptom” designates in particular attention disorders such asinattention, impulsivity, impatience, oppositional disorders, but alsodaytime or night-time motor hyperactivity, restless legs syndrome, andinsomnia.

Insomnia designates:

a. onset insomnia that is characterised by difficulties in fallingasleep;

b. maintenance insomnia that is characterised by night-time motorhyperactivity and waking up during the night, and

c. psychopathological insomnia, generally chronic and generally linkedto anxiety, stress and depressive episodes.

The criteria for evaluating the efficacy of the treatment ofattention-deficit/hyperactivity disorder by of the modified-releasepharmaceutical composition comprising mazindol optionally in associationwith iron and/or a psychostimulant in the treatment ofattention-deficit/hyperactivity disorder according to the presentinvention are the reduction (>30%) in the rating scale severity scorefor attention-deficit/hyperactivity symptoms AHD-RS (after 12 weeks oftreatment, and an improvement in severity scores for Conner's Parentquestionnaire (CPRS), Conner's Teacher questionnaire (CTRS) and CGI(clinical global impressions). Subjective somnolence is assessed usingthe CASS scale (child and adolescent somnolence scale). The quality offalling asleep is assessed by means of the restless legs syndromeseverity scale.

The patient according to the invention is chosen from among a newbornbaby, a child, an adolescent and an adult. According to a preferredembodiment, the patient is a child or an adolescent or an adult, evenmore preferably a child aged approximately 5 to 12 years. The patientaccording to the invention advantageously suffers iron deficiency, butis not anemic. Ferritin deficiency can be measured in the serum, butalso in all other biological fluids such as the cerebrospinal fluid.

A ferritin deficiency corresponds to a serum concentration of ferritinin the adult patient of less than approximately 50 μg/litre. Thisdeficit of iron storage” (expressed by a low ferritin level) may reachferritin concentrations of less than approximately 40 μg/l, or even lessthan approximately 35 μg/I, less than 30 μg/I, less than 20 μg/I, lessthan 15 μg/l, or even less than approximately 10 μg/l. The techniques ofdetermining serum ferritin are well known to persons skilled in the art.The immunoenzymatic method (IMX ferritin kit, Abbot Laboratories) can becited.

The patient according to the invention also has a normal serumconcentration of receptors soluble to transferrin. Transferrin isinvolved in the acquisition of iron by the cells of the organism; thisacquisition is controlled by the number of transferrin receptorsexisting on the cell surface. The concentration of these receptors canbe evaluated by techniques known to persons skilled in the art such asnephelemetry (Ruivard et al. 2000 Rev Méd Interne 21: 837-843). A normalrange of concentration of receptors soluble to transferrin is 2.0-4.50mg/l for men and 1.80-4.70 mg/I for women (see RsTF kit Ref 2148315 fromRoche).

According to another aspect of the present invention, mazindol is usedin combination with iron as a combination product for simultaneous,separate or sequential use.

According to a preferred method of use, the iron is used as a supplementwith the patient before the administration of mazindol. Within themeaning of the present invention, “iron” means iron in the form of aniron atom, iron salt or organic iron, or any formulation containing ironthat is pharmaceutically acceptable. By way of a non-exhaustive list,the pharmaceutically acceptable iron salt is selected from ferrous saltsand ferric salts, preferably from ferric ammonium citrate, ferricpyrophosphate, ferrocholinate, ferrous abscorbate, ferrous aspartate,ferrous chloride, ferrous sulphate, ferrous tartrate, ferrous fumarate,ferrous gluconate, ferrous gluceptate, ferrous sulphate glycine, ferrouslactate, ferrous oxalate and ferrous succinate.

According to a preferred embodiment of the invention, the iron salt isferrous sulphate, and preferably gastro-protected ferrous sulphate.

Alternatively, the pharmaceutical acceptable iron is in the form ofdextran iron, sucrose iron, poly-maltose iron, or sorbitol iron. Whenthe iron is in the form of pharmaceutically acceptable organic iron, itis preferably iron biglycinate, iron glycinate or iron proteinsuccinylate.

According to a preferred embodiment, the use of mazindol possibly inassociation with the iron according to the invention is implemented incombination with at least one compound selected from psychostimulants,as a combination product for simultaneous, separate or sequential use.

Psychostimulant compounds designate dopamine and/or noradrenaline uptakeinhibitors and agonists of catecholamines. Among these, the followingcan be cited non-exhaustively:

1) psychostimulant compounds: methylphenidate (speciality Ritalin®,Concerta®, Equasym®, Quasym, Medikinet Retard®), armodafinil (Nuvigil®),modafinil (Sparlon®, Modiodal®, Provigil®), atomoxetine (Strattera®),bupriopion, and amphetamines such as d-amphetamine, dexedrine,dexamphetamine and lisdexamfetamine (Vyvanse®, Elvanse®).

2) L-Dopa: Modopar, Sinemat

3) selective dopamine agonists: pramipexole (Sifrol®, Mirapex®),ropinirole (Requip®, Adartrel®), lisuride, pergolide, cabergoline, etc.

In particular, when mazindol is used in association with ferroussulphate, the quantity of ferrous sulphate administered to the patienton a daily basis is between 0.1 mg and 10 mg, preferably between 100 mgand 2 g per day, preferably approximately 500 mg, in one or more doses.

More particularly, according to the present invention, the patientsundergo iron supplementation, in particular ferrous sulphate, for 12weeks and the treatment with mazindol for 12 weeks.

According to the present invention, the composition may also compriseiron or one of its pharmaceutically acceptable salts and/or apsychostimulant.

In an embodiment of the invention, a controlled release formulation ofmazindol is provided containing immediate and sustained release layersin a layered tablet, which when ingested leads to an initial burst ofmazindol followed by a slower, continual release, for example, over 6-8hours (from ingestion) where it can be dissolved and absorbed in thesmall intestine, before it reaches the colon. The initial availabilityof mazindol is advantageous for ADHD patients because they need asufficient level of mental alertness and acuity at the beginning oftheir day so that they can concentrate, for instance, on work or drivingto work. Subsequently, the slower continual release and absorption ofmazindol in the intestine provided by the formulation of the presentinvention assures that adequate plasma concentrations are achievedthroughout the day and evening (e.g., for completion of the workday orhomework), while allowing the subject to fall asleep and remain asleepduring the night.

Data using the in vitro TIM gastrointestinal system (a dynamic,multi-compartmental system simulating the human stomach and smallintestines for studying the behavior of oral dosage strengths undervarious physiological gastrointestinal conditions) showed that theamount of mazindol that is bioaccessable, when formulated according tothe present invention, is similar under fasted and fed conditions;however, the Tmax in the fed state is delayed, compared to the fastedstate, by one hour or more, suggesting a food effect for mazindol. If arapid onset is sought, one would expect from these data that a patientmay have to wait about 2 hours after administration of mazindol beforehaving breakfast. Advantageously, however, using the formulation of thepresent invention in vivo, mazindol can be taken at significantly lesstime before consuming a meal (e.g., 30 minutes) and still obtain aninitial high release of mazindol in the stomach while not having tounnecessarily delay eating yet have a Tmax in the fed state that is notlater than in the fasted state. As discussed, this is particularlybeneficial for ADHD patients, for this initial amount of mazindolprovided increases patients' mental alertness and acuity at the start oftheir day (e.g., driving to work, starting school).

Konofal (2014) reported that there was no relationship between Cmax ofmazindol and efficacy or safety in children with ADHD. Unexpectedly, alower Cmax after administration of a mazindol formulation of the presentinvention can lead, without compromising efficacy, to a muted increasein the heart rate compared to administration of, for example, animmediate release formulation of mazindol. If the Cmax afteradministration of a formulation of the present invention is 20% to 40%lower than the Cmax after administering an immediate release formulationof mazindol, the increase in heart rate associated with mazindoladministration could surprisingly and unexpectedly be 4 to 11 beats/minless with the formulation of the present invention. This is a clinicallyrelevant and significant outcome.

EXAMPLES Example 1: Conditions for the Dissolution Profiles DissolutionMedium: 0.01N HCl Medium Volume: 500 mL USP Apparatus 2 (Paddles) Speed:50 rpm Medium Temperature: 37° C.±0.5° C.

Test 6 tablets (unless otherwise specified)Timepoints: 1, 2, 4, 6, and 8 hoursSample approximately 5 mL from each vessel using a syringe orautosampler with cannulae and a 10 μm full flow filter attached.

Example 2: Process for Manufacture of Mazindol Bilayer Tablets

A, Manufacturing Process for the Sustained Release (SR) Layer (2 mg.Tablet)1. Weigh the following ingredients: concentration w/w %

a. Mazindol 2.0 b. Lactose monohydrate NFIhypromellose NT (Retalac ®)97.0 c. Carbopol 971P 0.5 d. Magnesium stearate 0.5 Total = 100%2. Screen ingredients a, b, c, from step 1 into the V blender and blendfor 20 minutes.3. Pass the ingredients from Step 2 through the Comil.4. Add the ingredients from Step 3 into the V blender.5. Screen item d from Step 1 into the blender and blend for 5 minutes,6. Collect material from Step 5 for tablet manufacture.

B. Manufacturing Process for the Immediate Release (IR) Layer (2 mg)Tablet:

1. Weigh the following ingredients: concentration w/w %

a. Mazindol 2.0 b. Lactose monohydrate, NF 97.5 c. Magnesium stearate0.5 Total = 100%2. Screen ingredients a, b, from Step 1 into the V blender and blend for20 minutes3. Pass ingredients from Step 2 through the Comil4. Add ingredients from Step 3 into the V blender.5. Screen item c from Step 1 into the blender and blend for 5 minutes.6. Collect material from Step 5 for tablet manufacture.

C. Tablet Manufacture:

-   -   1. Set bilayer press for correct weight.    -   2. Add the IR blend to hopper 1.    -   3. Add the SR blend to hopper 2.    -   4. Compress tablets to a total weight of 100 mg.

Example 3: Dissolution Profiles of the Bilayer Tablets of Example 2

6 bilayer tablets have been prepared. Dissolution was performed per USPmonograph for Mazindol tablets.Data was collected using Pion Rainbow UV probes on n=3 tablets perbatch. % Release values are reported as the average of either two orthree tablets per prototype batch.The bilayer tablet formulations are based on two sustained release (SR)formulations and one immediate release (IR) formulation.The IR formulation is combined at three mass/mass ratios (IR/SR=50/50,60/40, & 70/30) with each SR formulation to create 6 bilayer tabletprototypes.The quantitative formulations for each of the prototype tablets aregiven in tables 1 and 2 along with their R&D batch number designation.Table-1 formulations include the SR formulation which utilizes HPMC andCarbopol 971P to modulate Mazindol dissolution and are categorized asSeries 1 prototype formulations.Table-2 formulations include the SR formulation which incorporates twodifferent molecular weight grades of HPMC to modulate Mazindoldissolution and are categorized as Series 2 prototype formulations.Table-3 reports the dissolution testing results for each of theprototype formulations.

TABLE 1 Series I Prototype Tablet Formulations Batch Number 100-15018100-15019 100-15020 IR layer/SR layer Ratio 50/50 60/40 70/30 IR LayerFormulation Ingredients mg/Tablet mg/Tablet mg/Tablet Mazindol 0.5 0.50.7 Lactose Monohydrate 49.25 59.1 68.95 Magnesium Stearate 0.25 0.30.35 SR Layer Formulation Mazindol 0.5 0.4 0.3 Lactose/HPMC K4M(Retalac ®) 49 39.2 29.4 Carbopol 971P 0.25 0.2 0.15 Magnesium Stearate0.25 0.2 0.15

TABLE 2 Series 2 Prototype Tablet Formulations Batch Number 100-15021100-15022 100-15023 IR layer/SR layer Ratio 50/50 60/40 70/30 IR LayerFormulation Ingredients mg/Tablet mg/Tablet mg/Tablet Mazindol 0.5 0.60.7 Lactose Monohydrate 49.25 59.1 68.95 Magnesium Stearate 0.25 0.30.35 SR Layer Formulation Mazindol 0.5 0.4 0.3 Lactose/HPMC K4M(Retalac ®) 36.75 29.4 22.05 HPMC K100M 12.5 10 7.5 Magnesium Stearate0.25 0.2 0.15

TABLE 3 Dissolution Results for Prototype Tablet Batches (UV ProbeAnalysis Data) Batch # 100- 100- 100- 100- 100- 100- 15018 15019 1502015021 15022 15023 Formulation Series 1 Series 2 IR/SR Ratio 50/50 60/4070/30 50/50 60/40 70/30 Time % % % % % % (Hours) Released ReleasedReleased Released Released Released 0.5 60.07% 63.29% 75.33% 64.81%69.79% 71.62% 1 69.01% 76.04% 87.15% 73.78% 78.84% 80.63% 1.5 74.97%80.03% 89.50% 80.00% 83.40% 83.91% 2 80.47% 84.20% 91.17% 84.32% 86.23%86.29% 3 86.31% 89.64% 95.69% 91.21% 91.58% 91.63% 4 90.87% 92.71%96.48% 94.11% 94.52% 94.44% 5 93.57% 94.78% 97.19% 96.40% 95.85% 95.21%6 95.47% 96.13% 97.49% 98.03% 97.09% 96.81% 7 96.48% 97.27% 99.30%98.58% 97.92% 97.72% 8 97.92% 98.80% 99.45% 99.06% 98.50% 99.39% 998.57% 99.61% 98.84% 99.91% 98.77% 98.94% 10 99.87% 99.44% 99.65% 99.77%99.36% 100.00%All prototype tablet batches were tested in two distinct dissolutionruns, one n=3 run analyzed using the UV probes and one n=4 run usingHPLC analysis.Table-4 reports the results for the n=3, UV analyzed dissolution testingcompared to the n=4, HPLC analyzed dissolution testing for batches100-15021 and 100-15022.

TABLE 4 UV Probe Analysis vs. HPLC Analysis of Dissolution Samples Batch# 100-15021 100-15022 Quantitation Time UV Probe HPLC UV Probe HPLC(hours) % Released % Released % Released % Released 1 73.78% 73.0%78.84% 73.4% 2 84.32% 87.6% 86.23% 88.5% 3 94.11% 95.8% 94.52% 94.5% 498.03% 98.0% 97.09% 96.3%The dissolution data for the prototype tablets reveal the Series 1formulations to have the greatest differentiation among the dissolutionprofiles at the early time points.The Series 2 formulations display a slighter differentiation at thesetime points for the range of SR/IR layer weight ratios.

REFERENCES

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1. A mazindol oral pharmaceutical unit dosage form in the form of amultilayer matrix-type tablet comprising: at least one immediate-release(IR) layer comprising mazindol and at least one diluent, at least onesustained-release (SR) layer comprising mazindol and at least onesustained-release, pH-independent and water-insoluble polymer, for atotal amount of mazindol comprised between 1 and 6 mg and a ratio inweight between the IR layers and the SR layers comprised between 40:60and 80-20 preferably between 50:50 and 70:30, more preferably of 50:50.2-12. (canceled)